Photo by Steven Harbour
Researchers say they have discovered a new subtype of acute lymphoblastic leukemia (ALL) that is sensitive to drugs already approved to treat other hematologic malignancies.
The team uncovered cases of ALL that were dependent upon tonic pre-B-cell-receptor (BCR) signaling and therefore sensitive to drugs that inhibit tyrosine kinases downstream of the pre-BCR.
The group also developed a test that can identify patients with this subtype of ALL.
“We hope patients in this newly identified subset can be treated with these targeted drugs, . . . which are powerfully effective in the mouse experiments we have conducted on ALL,” said Markus Müschen, MD, PhD, of the University of California, San Francisco.
Dr Müschen and his colleagues described this work in Cancer Cell.
The researchers studied samples from 830 patients enrolled in 4 ongoing ALL trials and found tonic pre-BCR signaling in 112 patients (13.5%). Virtually all of the bone marrow slices from these patients showed “beautiful staining” of BCL6 expression, Dr Müschen said. (Two of the patients had weak staining.)
On the other hand, no BCL6 staining was observed in patients lacking pre-BCR signaling. These results suggest that BCL6 is a biomarker for pre-BCR signaling. And by testing patients for BCL6, we may be able to identify those who will respond to treatment with pre-BCR signaling inhibitors, the researchers said.
The team tested a range of pre-BCR signaling inhibitors in vitro. And they found a few compounds that were effective against pre-BCR+ ALL—the SYK inhibitor PRT062607, the BTK inhibitor ibrutinib, the SRC inhibitor dasatinib, and the PIK3δ inhibitor idelalisib.
Subsequent experiments revealed that dasatinib had the strongest antileukemic effect, so the researchers tested the drug in mouse models of pre-BCR+ ALL. Dasatinib significantly delayed leukemic expansion and prolonged overall survival in some mice, while completely eradicating the disease in other mice.
Dr Müschen said that dasatinib and other pre-BCR signaling inhibitors may be able to reduce the amount of conventional chemotherapy given to patients with pre-BCR+ ALL, or even replace chemotherapy altogether.
“In our experiments with mice, both combination therapy with low-dose chemotherapy and single-agent targeted therapy each worked very well,” he said.
